Rafi A, Nagarkatti M, Nagarkatti P S
Department of Biology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg 24061, USA.
Blood. 1997 Apr 15;89(8):2901-8.
CD44 is a widely distributed cell surface glycoprotein whose principal ligand has been identified as hyaluronic acid (HA), a major component of the extracellular matrix (ECM). Recent studies have demonstrated that activation through CD44 leads to induction of effector function in T cells and macrophages. In the current study, we investigated whether HA or monoclonal antibodies (MoAbs) against CD44 would induce a proliferative response in mouse lymphocytes. Spleen cells from normal and nude, but not severe combined immunodeficient mice, exhibited strong proliferative responsiveness to stimulation with soluble HA or anti-CD44 MoAbs. Furthermore, purified B cells, but not T cells, were found to respond to HA. HA was unable to stimulate T cells even in the presence of antigen presenting cells (APC) and was unable to act as a costimulus in the presence of mitogenic or submitogenic concentrations of anti-CD3 MoAbs. In contrast, stimulation of B cells with HA in vitro, led to B-cell differentiation as measured by production of IgM antibodies in addition to increased expression of CD44 and decreased levels of CD45R. The fact that the B cells were responding directly to HA through its binding to CD44 and not to any contaminants or endotoxins was demonstrated by the fact that F(ab)2 fragments of anti-CD44 MoAbs or soluble CD44 fusion proteins could significantly inhibit the HA-induced proliferation of B cells. Also, HA-induced proliferation of B cells was not affected by the addition of polymixin B, and B cells from lipopolysaccharide (LPS)-unresponsive C3H/HeJ strain responded strongly to stimulation with HA. Furthermore, HA, but not chondroitin-sulfate, another major component of the ECM, induced B-cell activation. It was also noted that injection of HA intraperitoneally, triggered splenic B cell proliferation in vivo. Together, the current study demonstrates that interaction between HA and CD44 can regulate murine B-cell effector functions and that such interactions may play a critical role during normal or autoimmune responsiveness of B cells.
CD44是一种广泛分布的细胞表面糖蛋白，其主要配体已被确定为透明质酸（HA），它是细胞外基质（ECM）的主要成分。最近的研究表明，通过CD44激活可导致T细胞和巨噬细胞效应功能的诱导。在本研究中，我们调查了HA或抗CD44单克隆抗体（MoAbs）是否会诱导小鼠淋巴细胞的增殖反应。来自正常和裸鼠而非严重联合免疫缺陷小鼠的脾细胞，对可溶性HA或抗CD44 MoAbs刺激表现出强烈的增殖反应性。此外，发现纯化的B细胞而非T细胞对HA有反应。即使存在抗原呈递细胞（APC），HA也无法刺激T细胞，并且在有丝分裂原或亚有丝分裂原浓度的抗CD3 MoAbs存在时，HA也不能作为共刺激因子。相反，体外用HA刺激B细胞，除了增加CD44表达和降低CD45R水平外，还导致B细胞分化，这通过IgM抗体的产生来衡量。抗CD44 MoAbs的F(ab)2片段或可溶性CD44融合蛋白可显著抑制HA诱导的B细胞增殖，这一事实证明B细胞是通过HA与CD44的结合直接对HA作出反应，而不是对任何污染物或内毒素作出反应。此外，HA诱导的B细胞增殖不受多粘菌素B添加的影响，来自脂多糖（LPS）无反应性C3H/HeJ品系的B细胞对HA刺激有强烈反应。此外，HA而非ECM的另一种主要成分硫酸软骨素可诱导B细胞活化。还注意到腹腔注射HA可在体内引发脾B细胞增殖。总之，本研究表明HA与CD44之间的相互作用可调节小鼠B细胞效应功能，并且这种相互作用可能在B细胞的正常或自身免疫反应中起关键作用。
